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Inborn Errors of the Urea Cycle

Case:
Van J., born after a full-term pregnancy, was well during the first 36 hours following his
birth, but later he became lethargic and irritable and had hyperactive deep tendon
reflexes. He had no fever. A blood culture was done to rule out suspected sepsis.
Antibiotics were given.

Laboratory tests done showed the following:

- Serum electrolytes were within normal limits except for a slightly decreased HCO3- concentration
- Arterial blood pH = 7.5 (normal = 7.35 – 7.45)
- PCO2 = 25 torr (normal = 35 – 45 torr)
- Blood urea nitrogen (BUN) = 2 mg/dL (normal = 5 – 20 mg/dL

Chest x-ray was done because the baby was hyperventilating and it showed normal results.

For the next 24 hours, the lethargy progressed to stupor and then to coma, thus requiring mechanical
ventilation. Three days later, the infant was transferred to a newborn intensive care unit where the sepsis
workup (including a lumbar puncture) was repeated.

The head circumference was noted to be 2 cm greater than at birth. On day 5 at the ICU, the plasma
ammonium level was measured and found to be 1800 umol/L (normal = <35 umol/L). Cerebral edema was
revealed by magnetic resonance imaging. While awaiting the results of plasma amino acid analysis and urinary
orotic acid analysis, hemodialysis was started. Plasma amino acid values revealed a glutamine level of 1500
umol/L (normal = 550 – 650 umol/L); no detectable citrulline (normal = 10 – 30 umol/L); arginine level of 20
umol/L (normal = 40 – 80 umol/L). Urinary orotate was 100-fold greater than normal. After 4 hours, the plasma
ammonium had decreased to 150 umol/L. However, the baby remained in deep coma with no evidence of
spontaneous respiration or neurological function. Van J. died at 7 days of age. Postmortem analysis of hepatic
ornithine transcarbamylase (OTC) activity revealed it to be < 2% of normal. A review of the family history
showed that two of the mother’s brothers had died in coma within the first week of life and a diagnosis of
encephalitis had been given as the cause of death.

GUIDE QUESTIONS:
1. Review the urea cycle.
2. What are the inborn errors associated with deficiency of each enzyme of the urea cycle?
3. Describe the similarities and differences in manifestations and laboratory findings between the different
inborn errors of the urea cycle.
4. In the above case, what are the important manifestations and laboratory findings that support a
diagnosis of OTC deficiency? Explain the biochemical basis of each manifestation and the rationale
behind each laboratory test.
5. Discuss the treatment of the different inborn errors of urea synthesis.

I. Objectives (Oflash)
1
 II. Urea Cycle (Oflash)
III. Pathophysiology
IV. Risk factors
V. Inborn Errors of Urea Cycle (Reyes, Perdido)
A. Enzymes (5)
B. Transporters (3)
C. Activator (1)
VI. Manifestations & Complications (Kai)
VII. Diagnostic Procedures/Laboratory Tests (Lazaro)
VIII. Prevention & Treatment (Claire)
IX. Case Study (Reyes, Perdido)

OBJECTIVES

1. Discuss the urea cycle.

2. Differentiate the inborn errors associated with the urea cycle.
3. Describe the similarities and differences in manifestations and laboratory findings between the different inborn
errors of the urea cycle.
4. Explain the manifestations that were presented in the above case that support the diagnosis of OTC deficiency.
5. Describe the different laboratory tests that were done to diagnose the above case and give the rationale behind
each test.
6. Discuss the treatment of the different inborn errors of urea synthesis.

UREA CYCLE

UREA
- Urea represents the final end product of protein metabolism in the human body. The amount of urea
excreted in the urine is directly proportional to one’s protein intake.
- Urea is synthesized almost exclusively in the liver. It is the disposal form of ammonia, which is toxic to the
brain and CNS. Normally, only 30 – 60 uM of ammonia is present in the blood. It is rapidly removed from the
blood and converted by the liver to urea.
- a major form of disposal of amino groups derived from amino acids
- produced by the liver to create a metabolite of ammonia (nitrogen) that can be excreted in the urine
- Ammonia (NH3) is a small metabolite that results predominantly from protein and amino acid degradation. It is
highly membrane-permeant and readily crosses epithelial barriers in its nonionized form.
- Excreted to the KIDNEYS
- accounts for about 90% of the nitrogen-containing components of urine
- major end product of nitrogen catabolism in humans
UREA CYCLE
- Also known as Krebs-Henseleit Cycle
- The urea cycle is the process of removal of ammonia from the human body. It has a five-step cyclic
process with five distinct enzymes. The first two occur inside the mitochondria whereas the remaining cycle
takes place in the cytosol.
- Conversion of ammonia into urea through a series of biochemical reactions
IN MITOCHONDRIA:
1. Formation of carbamoyl phosphate
- Formation of carbamoyl phosphate by carbamoyl phosphate synthetase I (CPS I) is driven by cleavage of two
molecules of ATP
- Ammonia incorporated into carbamoyl phosphate is provided primarily by the oxidative deamination of
glutamate by mitochondrial glutamate dehydrogenase.
- Ultimately, the nitrogen atom derived from this ammonia becomes one of the nitrogens of urea.
- CPS I requires N-acetylglutamate as a positive allosteric activator
2. Formation of citrulline
- The carbamoyl portion of carbamoyl phosphate is transferred to ornithine by ornithine transcarbamoylase

2
 (OTC) as the high-energy phosphate is released as inorganic phosphate.
- The reaction product, citrulline, is transported to the cytosol.
TAKE NOTE: The ornithine came from cytosol and enters the mitochondria using a transport system: ORNITHINE
TRANSPORTER GENE
IN CYTOSOL:
3. Synthesis of argininosuccinate:
- Argininosuccinate synthetase combines citrulline with aspartate to form argininosuccinate.
- The α-amino group of aspartate provides the second nitrogen that is ultimately incorporated into urea.
- The formation of argininosuccinate is driven by the cleavage of ATP to adenosine monophosphate and
pyrophosphate.
- This is the third and final molecule of ATP consumed in the formation of urea
4. Cleavage of argininosuccinate:
- Argininosuccinate is cleaved by argininosuccinate lyase to yield arginine and fumarate.
- The arginine formed by this reaction serves as the immediate precursor of urea.
- Fumarate produced in the urea cycle is hydrated to malate, providing a link with several metabolic pathways.
- For example, the malate can be transported into the mitochondria via the malate–aspartate shuttle, reenter the
tricarboxylic acid cycle, and get oxidized to oxaloacetate, which can be used for gluconeogenesis.
- Alternatively, the oxaloacetate can be converted to aspartate via transamination and can enter the urea cycle
5. Formation of Urea and reformation
of Ornithine

IN MITOCHONDRIA IN CYTOSOL

1. Formation of Carbamoyl Phosphate 1. Synthesis of Argininosuccinate

2. Formation of Citrulline 2. Cleavage of Argininosuccinate

3. Formation of Urea and reformation of

Ornithine

ENZYMES TRANSPORTERS ACTIVATOR

carbamoyl phosphate synthetase I Ornithine Translocase N-acetylglutamate

(CPS I)

ornithine transcarbamylase (OTC) Citrin

3
 argininosuccinate synthetase amino acid transporter

argininosuccinate lyase

arginase

PATHOPHYSIOLOGY

● Urea cycle disorders are congenital metabolic errors stemming from flaws in one of the enzymes or
transporter molecules responsible for eliminating ammonia from the bloodstream in the liver.
Typically, ammonia is converted into urea, which is then excreted by the kidneys. Consequently,
these disorders result in an accumulation of toxic ammonia, particularly detrimental to the central
nervous system. Infants with severe mutations in any of the first four urea cycle enzymes can rapidly
deteriorate within 36 to 48 hours after birth, even if they initially appear healthy. This can lead to
discharging newborns from the hospital before symptoms manifest, potentially causing undetected
issues later. Detecting elevated ammonia levels is crucial in diagnosing urea cycle disorders, and
treatment should begin promptly, even before obtaining a definitive diagnosis

RISK FACTORS

Common risk factors for Urea Cycle Disorders include:

1. Genetics: UCDs are primarily caused by mutations in genes responsible for the urea cycle. A family
history of UCD increases the risk.
2. Consanguinity: Marriages between close relatives may increase the risk of passing on recessive
UCD genes.
3. Gender: Some UCDs may be more common in one gender than the other.
4. Age: UCD symptoms can present at any age, but they often become apparent in infancy or early
childhood.
5. Specific UCD Type: Each UCD has its own unique risk factors, depending on which enzyme in the
urea cycle is affected.

INBORN ERRORS OF UREA CYCLE

Error in Enzyme
1. Hyperammonemia 1
○ Enzyme Deficient: Carbamoyl Phosphate Synthetase 1
○ Chromosome 2 Autosomal Recessive
○ Increased: Ammonia, Plasma glutamine, Alanine
i. Without functional CPS1, ammonia cannot be efficiently converted to urea, resulting in elevated
ammonia levels.
ii. Excess ammonia will also result in the increased formation of glutamine. Glutamine synthetase
uses the reactants ammonia and glutamate to yield glutamine.
iii. Alanine is another amino acid that can help transport excess ammonia from peripheral tissues
to the liver for detoxification. Elevated alanine levels may occur as a response to the increased
ammonia in the body.
○ Decreased: Citrulline, Arginine
i. Decreased citrulline and arginine levels occur downstream in the urea cycle, as they cannot be

4
 synthesized properly due to the initial deficiency.
2. Hyperammonemia 2
○ Enzyme Deficient: Ornithine Transcarbamoylase
○ X chromosome, X-linked
○ Increased: Ammonia, Plasma glutamine, Alanine, Orotate
i. Excess ammonia will also result in the increased formation of glutamine. Glutamine synthetase
uses the reactants ammonia and glutamate to yield glutamine.
ii. Alanine is another amino acid that can help transport excess ammonia from peripheral tissues
to the liver for detoxification. Elevated alanine levels may occur as a response to the increased
ammonia in the body.
iii. This enzyme deficiency leads to increased levels of carbamoyl phosphate, which becomes
shunted into the pyrimidine synthesis pathway once carbamoyl phosphate enters the
cytoplasm. Carbamoyl phosphate is converted into orotic acid.
○ Decreased: Citrulline, Arginine
i. Decreased citrulline and arginine levels occur downstream in the urea cycle, as they cannot be
synthesized properly due to the initial deficiency.
3. Citrullinemia
○ Enzyme Deficient: Argininosuccinate synthetase
○ Chromosome 9: ASS1 gene; Autosomal Recessive
○ Type 1- Classical ; at any age
i. Type I citrullinemia (also known as classic citrullinemia) usually becomes evident in the first few
days of life.
ii. Affected infants typically appear normal at birth, but as ammonia builds up, they experience a
progressive lack of energy (lethargy), poor feeding, vomiting, seizures, and loss of
consciousness. Some affected individuals develop serious liver ​problems.
○ Increased: Ammonia, Citrulline, Orotate
i. Deficiency in Argininosuccinate synthetase means that citrulline cannot combine with aspartate
to form argininosuccinate; thus accumulation of citrulline.
ii. There can be an increased diversion of carbamoyl phosphate, a molecule from the urea cycle,
into the pyrimidine synthesis pathway. This can lead to elevated orotate levels.
○ Decreased: Arginine
i. Conversion of citrulline to arginine cannot occur efficiently. As a result, arginine levels
decrease.
4. Argininosuccinic aciduria
○ Enzyme Deficient: Argininosuccinase/ Argininossucinate Lyase
○ Chromosome 7, Autosomal Recessive
○ Trichorrhexis Nodosa
i. common in late onset, presenting as coarse, brittle hair and is the result of arginine deficiency
○ Increased: Ammonia, Citrulline, Orotate, Argininosuccinate
i. argininosuccinate lyase enzyme cannot convert argininosuccinate into arginine and fumarate,
causing citrulline and argininosuccinate to accumulate in the blood.
ii. There can be an increased diversion of carbamoyl phosphate, a molecule from the urea cycle,
into the pyrimidine synthesis pathway. This can lead to elevated orotate levels.
○ Decreased: Arginine
i. Without argininosuccinase, argininosuccinate cannot be converted into arginine and fumarate.
Thus, arginine is decreased
5. Argininemia
○ Enzyme Deficient: Arginase
○ Autosomal Recessive
○ Episodic hyperammonemia
○ Spastic diplegia
○ Increased: Ammonia, Arginine, Orotate
i. As arginine cannot be converted to urea, arginine accumulates
ii. There can be an increased diversion of carbamoyl phosphate, a molecule from the urea cycle,
into the pyrimidine synthesis pathway. This can lead to elevated orotate levels.

Disorder Enzyme Deficient Increased Decreased

5
 Hyperammonemia 1 Carbamoyl Phosphate Ammonia, Plasma Citrulline, Arginine,
Synthetase 1 glutamine, Alanine Orotate

Hyperammonemia 2 Ornithine Transcarbamoylase Ammonia, Plasma Citrulline, Arginine

glutamine, Alanine,
Orotate

Citrullinemia Argininosuccinate synthetase Ammonia, Citrulline, Argininosuccinate,

Orotate Arginine

Argininosuccinic aciduria Argininosuccinase/ Ammonia, Citrulline, Arginine

Argininossucinate Lyase Orotate,
Argininosuccinate

Argininemia Arginase Ammonia, Arginine,

Orotate

Error in Transporters
1. Hyperornithinemia - Hyperammonemia - Homocitrullinuria (HHH) Syndrome
○ Homocitrullinuria, hyperammonemia and hyperornithinemia
○ It is due to mutation of the ORNT1 gene that encodes the mitochondrial membrane ornithine
transporter. No transport of ornithine → urea cycle becomes inoperable → hyperammonemia,
hyperornithinemia and homocitrullinuria occurs.
2. Citrullinemia 2
○ Citrin deficiency encoded by SLC25A1​3 gene.
○ Due to deficiency of citrin protein which is involved in transporting aspartate and glutamate in the inner
mitochondrial membrane
○ Type 2- Adults ; NICCD
i. chiefly affects the nervous system,
ii. can be triggered by certain medications, infections, surgery, and alcohol intake.
iii. may also develop in people who as infants
iv. had a liver disorder called ​neonatal intrahepatic cholestasis caused by citrin deficiency
(NICCD)​. NICCD blocks the flow of ​bile​and prevents the body from processing certain
nutrients properly.
○ Results to impaired urea cycle function which increases citrulline levels
3. Hyperdibasic aminoaciduria (Dibasic Amino Acid Transporter)
○ leads to the excessive loss of certain amino acids in the urine, particularly the dibasic amino acids
cystine, ornithine, arginine, and lysine (abbreviated as COAL amino acids).

Disorder Transporter Affected Increased

Hyperornithinemia - Ornithine mitochondrial transporter Ammonia, plasma ornithine,

Hyperammonemia - Homocitrullinuria homocitrulline
(HHH) Syndrome

Citrullinemia 2 Citrin Ammonia, plasma citrulline

Hyperdibasic aminoaciduria (Dibasic Dibasic amino acid transporter Ammonia, urine lyine, arginine,
Amino Acid Transporter) ornithine

Error in Activator
6
 1. Deficiency in N-Acetylglutamate synthase (N-Aga)
○ Deficiency in activator of CPS1.
○ No synthesis of Carbamoyl phosphate.
○ Nothing will bind to Orothine.
○ No citrulline will be produced.

Disorder Activator Deficient Increased Decreased

Deficiency in N-Aga Ammonia, glutamine, Citrulline, arginine

N-Acetylglutamate ornithine
synthase (N-Aga)

Disorder Enzyme Deficient Manifestation Treatment

Hyperammonemia 1 Carbamoyl Phosphate
Synthetase 1
Complete deficiency of CPS1 sodium benzoate and arginine
causes death in newborn
infants. Survivors are often
intellectually disabled and
suffer frequent
hyperammonemic crises
during intercurrent illness or
other catabolic stresses.

Hyperammonemia 2 Ornithine Transcarbamoylase sodium benzoate plus sodium

Males with severe deficiency phenylacetate, IV nitrogen
typically present within 24–72 scavengers, oral
hours after birth with severe

7
 hyperammonemia and phenylbutyrate, L-Citrulline,
encephalopathy. Arginine
Males and females with partial
OTC deficiency may present
at any age and may have
normal development.

Citrullinemia Argininosuccinate synthetase life-threatening restriction of protein intake

hyperammonemia, fatty and the administration of oral
metamorphosis, focal phenylbutyrate and oral
necrosis, and patchy arginine
cholestasis in the liver.

Argininosuccinic aciduria Argininosuccinase/ Hepatomegaly, Trichorrhexis administration of arginine and

Argininossucinate Lyase nodosa phenylbutyrate

Argininemia Arginase progressive mental and benzoate, phenylacetate, and

neurologic deterioration; a protein restricted diet
spasticity

Disorder Transporter / Activator Defect Manifestation Treatment

Hyperornithinemia - Ornithine mitochondrial post-prandial or intermittent protein restricted diet, with

Hyperammonemia - transporter hyperammonemia lysine, ornithine or citrulline
Homocitrullinuria (HHH) supplementation
Syndrome

Citrullinemia 2 Citrin cyclical erratic behavior, nitrogen-scavengers (arginine

dysarthria, seizures, and phenylbutyrate) and liver
weakness, and coma. transplant.

aminoacidemia, galactosemia,
hypoproteinemia, and
hypoglycemia.

Deficiency in N-Aga Patients with complete NAGS
N-Acetylglutamate synthase deficiency rapidly develop
(N-Aga) hyperammonemia in the
newborn period. Patients who
are successfully rescued from
crisis are chronically at risk for
repeated bouts of
hyperammonemia.
sodium benzoate plus sodium
phenylacetate, IV nitrogen
scavengers, oral
phenylbutyrate, L-Citrulline,
Arginine,
N-carbamylglutamate
supplementation

MANIFESTATIONS

The liver catabolizes toxic ammonia into urea. When unable to undergo this process, ammonia continues to accumulate
in the body, causing it to become toxic. There are six clinically relevant disorders that result in the increased ammonia
and decreased urea in the blood, which also present the same clinical manifestations.

Hyperammonemia - a condition caused by increased ammonia which is toxic to the brain and may lead to
encephalopathy; this can manifest as cerebral edema, vomiting, blurred vision, asterixis, and seizures.

Early Signs of Urea Cycle disorder

● Lethargy or feeling tired

8
 ● Nausea or vomiting
● Cannot eat or feed
● Breathing too fast or too slow
● Confusion

Mild to Severe:
● Problems with cognitive development and intellectual challenges
● Behavioral changes
● Developmental delays
● Cerebral edema
● Spasticity
● seizures

COMPLICATIONS

Ammonia is a highly toxic substance in the body once accumulated and not removed. If this condition is left untreated,
the increased amounts of ammonia in the bloodstream will cause brain damage, coma, and worse, death.

DIAGNOSTIC PROCEDURES/LABORATORY TESTS

Tests to diagnose urea cycle disorder include:

● Amino acid profile or analysis: A blood or urine sample is taken to measure the amino acids that the body
metabolizes
● Liver biopsy: A small piece of liver is removed to identify the type of UCD, highlight the genetic changes that
cause the disorder, and can confirm the diagnosis.
● Magnetic Resonance Imaging (MRI) or CT scan: It is done to see if there is swelling of the brain caused by
the ammonia in the blood.
● Plasma Ammonia Level: Measurement of plasma ammonia concentration is one of the most critical tests in
diagnosing and monitoring UCDs. Elevated ammonia levels are a hallmark of UCDs and indicate impaired
ammonia detoxification. High ammonia levels can lead to neurological symptoms and damage, so monitoring
them is crucial for patient management.
● Plasma Amino Acid Analysis: This test assesses the levels of amino acids in the blood. UCDs can lead to
specific alterations in amino acid profiles, such as elevated levels of citrulline and ornithine and decreased
levels of arginine. These abnormalities can help in the diagnosis of specific UCDs.
● Urinary orotic Acid: Elevated levels of orotic acid in the urine can be indicative of ornithine transcarbamylase
deficiency, a specific UCD. This test can aid in the differential diagnosis of UCDs.
● Genetic Testing: DNA analysis can confirm the specific genetic mutations responsible for the UCD and provide
information about the underlying genetic defect. This can be important for genetic counseling and identifying
potential carriers within the family.
● Liver Function Tests: These tests assess the liver's ability to produce the enzymes necessary for the urea
cycle. Abnormal liver function tests may suggest a liver-related UCD, such as ornithine transcarbamylase
deficiency.
● Molecular Genetic Testing of Family Members: If a specific mutation is identified in an affected individual,
genetic testing of family members can help identify carriers or individuals at risk for UCDs. This is important for
family planning and early intervention.

PREVENTION & TREATMENT

Treatment for urea cycle disorder focuses on lowering the amount of ammonia in your blood, which could include:

● Eating a diet low in protein. If you eat a diet low in protein, you reduce your risk of building up ammonia in
your blood.
Normal: 1-1.5g/kg of body weight/day
○ Low protein diet: 0.7g/kg of body weight/day for Hgb, plasma protein, enzyme synthesis
○ Provide calories from carbs and fats to meet energy requirement
● Hemodialysis: to filter ammonia out of the blood

9
 ● Binding compounds that includes phenylacetate and sodium benzoate (Ammonul ®) to remove ammonia
from your blood.
○ binding compounds bind with amino acids, making it water-soluble and excreted in the urine
○ Phenylacetate + Glutamine = Phenylacetylglutamine via glutamine-N-acetyltransferase
○ Sodium benzoate + Glycine = Hippuric acid via glycine-N-acyltransferase
○ Hippuric acid & Phenylacetylglutamine are water-soluble and normally seen in urine
● Taking amino acid supplements (arginine or citrulline) to encourage your body to complete the urea cycle.
○Citrulline: absent due to OTC deficiency; to continue urea cycle
○ Arginine: becomes essential due to Urea Cycle defect
■ Except for cases of Argininemia (excessive arginine)
● Antibiotics: to kill harmless bacteria that produce ammonia
● Lactulose: reduces ammonia absorption through increased GI motility, making it excreted in th stool.
● Severe cases of hyperammonemia could lead to a liver transplant.
● Administration of Glutamate to prevent Coma
○ Cause of coma: depletion of a-Ketoglutarate from Krebs Cycle to produce Glutamate
○ Administer GLUTAMATE → no need to get a-Ketoglutarate from Krebs Cycle
○ a-Ketoglutarate stays in Krebs Cycle → ATP production continues → NO COMA

You can’t prevent urea cycle disorder since it’s a genetic condition. If you plan on becoming pregnant and want to
understand the risks of having a child with a genetic condition, talk to your provider about genetic testing.

Despite these therapeutic advances, many UCDs remain difficult to treat, and liver transplantation is eventually
required for many patients. Timing of liver transplantation is critical. Optimally, the infant should grow to an age
when transplantation is less risky (> 1 year), but it is important to not wait so long as to allow an intercurrent
episode of hyperammonemia (often associated with illness) to cause irreparable harm to the central nervous
system.

CASE STUDY

In the provided case, numerous clinical indicators strongly support the diagnosis of Ornithine Transcarbamylase (OTC)
deficiency. These clinical observations correspond closely with the typical signs and complications associated with this
congenital metabolic disorder:

Manifestations:

● lethargic and irritable

● had hyperactive deep tendon reflexes
● Slightly decreased HCO3- concentration
● Arterial blood pH = 7.5 (normal = 7.35 – 7.45)
● PCO2 = 25 torr (normal = 35 – 45 torr)
● Blood urea nitrogen (BUN) = 2 mg/dL (normal = 5 – 20 mg/dL)
● Hyperventilation
● For the next 24 hours, the lethargy progressed to stupor and then to coma
● The head circumference was noted to be 2 cm greater than at birth.
● On day 5 at the ICU, the plasma ammonium level of 1800 umol/L (normal = <35 umol/L).
● Cerebral edema through magnetic resonance imaging.
● While awaiting the results of plasma amino acid analysis and urinary orotic acid analysis,
hemodialysis was started.
● Glutamine level of 1500 umol/L (normal = 550 – 650 umol/L)
● no detectable citrulline (normal = 10 – 30 umol/L);
● arginine level of 20 umol/L (normal = 40 – 80 umol/L).
● Urinary orotate was 100-fold greater than normal.

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 ● After 4 hours, the plasma ammonium had decreased to 150 umol/L. However, the baby remained in
deep coma with no evidence of spontaneous respiration or neurological function. Van J. died at 7
days of age.
● Postmortem analysis of hepatic ornithine transcarbamylase (OTC) activity revealed it to be <
2% of normal. A review of the family history showed that two of the mother’s brothers had died in
coma within the first week of life and a diagnosis of encephalitis had been given as the cause of
death.
Edited:

Patient Information:

● Name: Van J.
● Age: Newborn (7 days old)
● Birth history: Born after a full-term pregnancy

Chief Complaint:

● Lethargy, irritability, hyperactive deep tendon reflexes

History of Present Illness:

● Initially well during the first 36 hours after birth

● Developed lethargy, irritability, and hyperactive deep tendon reflexes
● No fever observed
● Blood culture done to rule out suspected sepsis
● Started antibiotics

Past Medical History:

● No specific past medical history provided, but there is a family history of two maternal brothers who
died in coma within the first week of life, with a diagnosis of encephalitis as the cause of death.

Social History:

● No specific social history information provided in the case study.

Family History:

● Two of the mother's brothers had died in coma within the first week of life, and the cause of death
was diagnosed as encephalitis.

Current Medication List:

● Antibiotics (not specified)

Lab Works:

TEST PROCEDURE RESULT REFERENCE RANGE HIGH/LOW/N

11
 ORMAL

Serum Electrolytes ● not specifically SLIGHTLY

indicated DECREASED
● within normal 1. Sodium (Na+): 135-145 HCO3-
limits milliequivalents per liter
● Slightly (mEq/L)
decreased 2. Potassium (K+):
HCO3- ○ 3.5-5.0 milliequivalents
concentration per liter (mEq/L)
3. Chloride (Cl-):
○ Normal Range: 95-105
milliequivalents per liter
(mEq/L)
4. Bicarbonate (HCO3-):
○ Normal Range: 22-28
milliequivalents per liter
(mEq/L)
5. Calcium (Ca2+):
○ Normal Range:
8.4-10.2 milligrams per
deciliter (mg/dL)
6. Magnesium (Mg2+):
○ Normal Range: 1.5-2.5
milligrams per deciliter
(mg/dL)

Arterial Blood pH 7.5 NORMAL

7.35 – 7.45

PCO2 25 torr NORMAL

35 – 45 torr

Blood Urea Nitrogen 2 mg/dl NORMAL

5 – 20 mg/dL

Plasma ammonium 1800 umol/L HIGH

<35 umol/L

Plasma amino acid: GLUT = 1500 umol/L GLUT = 550-650 umol/L HIGH
- Glutamine CIT = not detectable CIT = 10-30 umol/L NOT
- Citrulline ARG = 20 umol/L ARG = 40-80 umol/L DETECTABL
- Arginine E
LOW

Urinary orotate

12
 Post-mortem analysis
of OTC

● Urinary orotate was 100-fold greater than normal.

● Postmortem analysis of hepatic ornithine transcarbamylase (OTC) activity revealed it to be < 2% of
normal.

Problem List:

● Lethargy and irritability

● Hyperactive deep tendon reflexes
● Altered blood chemistry, including metabolic alkalosis and decreased PCO2
● Elevated plasma ammonium level
● Cerebral edema
● Diagnosis of ornithine transcarbamylase (OTC) deficiency

Treatment (TK - To Know):

● Van J. received antibiotics initially.

● Hemodialysis was started.
● The plasma ammonium had decreased to 150 umol/L after 4 hours.
● Despite treatment, the baby remained in a deep coma with no evidence of spontaneous respiration or
neurological function and eventually died at 7 days of age.

1. Lethargy and Irritability: Initially, the emergence of lethargy and irritability aligns with the early indications of OTC
deficiency. As ammonia levels surge, the central nervous system is impacted, causing neurological dysfunction and
behavioral alterations.

2. Hyperactive Deep Tendon Reflexes: The presence of intensified deep tendon reflexes signifies neurological
involvement linked to hyperammonemia. Escalated ammonia levels can induce restlessness and heightened
neurological excitability, leading to augmented reflex responses. This connection is corroborated by information found in
clinical directives and research papers pertaining to urea cycle disorders.

3. Metabolic Alkalosis: The arterial blood pH of 7.5 and reduced PCO2 (25 torr) suggest the presence of metabolic
alkalosis. This arises from the urea cycle's diminished capacity to counteract excess ammonia. As ammonia
accumulates, it associates with bicarbonate, prompting the observed alkaline state.

4. Elevated Plasma Ammonium Level: The conspicuous elevation of plasma ammonium levels to 1800 umol/L (with a
normal range of <35 umol/L) indisputably signifies hyperammonemia, a defining characteristic of OTC deficiency. The
benchmark values for normal ammonia concentrations are established in accordance with clinical guidelines and
well-recognized laboratory criteria.

5. Neurological Complications: The transition from lethargy to stupor and eventual coma, necessitating mechanical
ventilation, accentuates the severity of neurological involvement precipitated by hyperammonemia. This deterioration in
neurological function is a well-documented complication of OTC deficiency.

6. Cerebral Edema: Magnetic resonance imaging indicating the presence of cerebral edema underscores the grave
neurological repercussions of hyperammonemia. This finding further bolsters the likelihood of OTC deficiency and is
expounded upon within the context of urea cycle disorders in clinical literature.

7. Family History: The familial precedent of two maternal siblings succumbing to coma within the first week of life, with

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an initial diagnosis of encephalitis, raises suspicions regarding an inherent genetic disorder.

In summation, the clinical indicators observed in this case, spanning from lethargy and irritability to heightened reflexes,
metabolic alkalosis, elevated plasma ammonium levels, profound neurological complications, cerebral edema, and the
familial medical history, collectively reinforce the likelihood of OTC deficiency—a widely documented congenital
anomaly within the urea cycle. These clinical observations closely align with the well-established pathophysiology and
clinical presentation of OTC deficiency, as detailed in recognized medical references and clinical protocols.

TESTS IN THE CASE STUDY RATIONALE

1. Serum Electrolytes, Arterial Blood pH, and PCO2:

○ w/in normal limits except for decreased bicarbonate concentration
○ No electrolyte imbalance
○ Arterial blood pH = 7.5 (​ALKALOTIC​due to hyperventilation)
○ PCO2 = 25 torr (​ALKALOTIC​due to hyperventilation)
○ Hyperammonemia​- due to OTC deficiency → cannot complete Urea Cycle
○ Purpose: These tests were performed to assess the infant's electrolyte levels and acid-base balance.
The abnormal arterial blood pH (alkalosis) and PCO2, along with reduced bicarbonate (HCO3-) levels,
suggest a metabolic alkalosis, potentially related to metabolic issues like urea cycle disorders.
○ Reference: Pediatric Critical Care Medicine's Chapter on Acid-Base Disorders (2006).
2. Blood Urea Nitrogen (BUN):
○ BUN = 2 mg/dL (​LOW​due to incomplete urea cycle)
○ - Reason: BUN levels were measured to evaluate kidney function and nitrogen metabolism. The low
BUN level of 2 mg/dL may indicate impaired urea cycle function or excessive ammonia elimination.
○ - Source: Nelson Textbook of Pediatrics, Chapter on Evaluation of Renal Function, Fluid, and
Electrolyte Balance (2019).
3. Plasma Amino Acid Analysis and Urinary Orotic Acid Analysis
○ Glutamine​= 1500 umol/L (​hyperglutaminemia​)
○ Citrulline​= none detected (product of reaction that uses OTC)
○ Arginine​= 20 umol/L (product of 4th reaction in urea cycle)
■ No longer produced by body → semi-essential becomes essential
○ Intention: These tests are vital for diagnosing specific inborn errors of metabolism, including urea cycle
disorders. Elevated glutamine, low citrulline, low arginine, and increased urinary orotic acid levels
suggest a potential OTC deficiency.
○ Source: "Inborn Metabolic Diseases: Diagnosis and Treatment" by J. Fernandes and J. Saudubray
(2016).
4. Plasma Ammonium Level:
○ Plasma NH4+ = 1800 umol/L → ​hemodialysis​→ 150 umol/L
○ Hemodialysis:
■ Reasoning: Hemodialysis was initiated to rapidly eliminate excess ammonia from the
bloodstream.
■ Reference: "Pediatric Nephrology," Chapter on Pediatric Dialysis (2018
○ Objective: Measuring plasma ammonium levels is crucial for diagnosing hyperammonemia, a key
characteristic of urea cycle disorders. Elevated levels may suggest impaired ammonia metabolism.
○ Source: "Inborn Metabolic Diseases: Diagnosis and Treatment" by J. Fernandes and J. Saudubray
(2016).
○ Plasma Ammonium Level:
■ Plasma NH4+ = 1800 umol/L → ​hemodialysis​→ 150 umol/L
■ Hemodialysis:
● Reasoning: Hemodialysis was initiated to rapidly eliminate excess ammonia from the
bloodstream.
● Reference: "Pediatric Nephrology," Chapter on Pediatric Dialysis (2018
■ Objective: Measuring plasma ammonium levels is crucial for diagnosing hyperammonemia, a
key characteristic of urea cycle disorders. Elevated levels may suggest impaired ammonia
metabolism.
■ Source: "Inborn Metabolic Diseases: Diagnosis and Treatment" by J. Fernandes and J.
Saudubray (2016).
5. Urinary orotate

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 ○ 100-fold greater than normal
○ Normal​: carbamoyl phosphate combines w/ ornithine (via OTC)
○ OTC is absent
○ Orotic aciduria from accumulation of Carbamoyl Phosphate → enter pyrimidine synthesis pathway
(alternative) and combines w/ aspartate
○ Form ​first pyrimidine ring = orotate

6-10 are tests that were done that has little significance to the disease

6. Blood Culture
○ Reason: A blood culture was conducted to rule out the possibility of sepsis since the infant initially
displayed symptoms like lethargy and irritability, which can also occur with bacterial sepsis
7. Postmortem Analysis of Hepatic OTC Activity:
○ Purpose: Postmortem analysis of hepatic OTC activity was performed to confirm the diagnosis of OTC
deficiency, which was suspected based on clinical and laboratory findings.
○ Source: "Molecular Genetics and Metabolism," Volume 100, Supplement 1, Pages S31-S41 (2010).
8. Chest X-ray:
○ - Basis: A chest x-ray was ordered due to the infant's hyperventilation, with the aim of ruling out any
pulmonary abnormalities.
○ Reference: Radiology's Chapter on Chest Radiography (2017).
9. Magnetic Resonance Imaging (MRI):
○ Purpose: An MRI was conducted to evaluate the brain and identify signs of cerebral edema. This helps
assess the extent of neurological damage, which is often seen in cases of severe hyperammonemia.
○ Reference: "Magnetic Resonance Imaging of the Brain and Spine," Chapter on Basic Principles of MRI
(2019).
10. Lumbar puncture
○ A lumbar puncture is a procedure that involves inserting a thin needle into the spinal canal to collect
cerebrospinal fluid (CSF). CSF is the fluid that surrounds the brain and spinal cord. A lumbar puncture
is typically performed to rule out meningitis, encephalitis, and other infections of the central nervous
system.

These laboratory tests, combined with clinical observations and family history, contributed to the diagnosis of ornithine
transcarbamylase (OTC) deficiency in the infant and highlighted the severe consequences of this condition. Early
diagnosis and intervention are crucial for managing such inborn errors of metabolism and preventing fatal outcomes.

REFERENCES

Inborn Metabolic Diseases: Diagnosis and Treatment" authored by J. Fernandes and J. Saudubray.

"Metabolic and Molecular Bases of Inherited Disease," edited by Charles R. Scriver, et al.

Surviving Sepsis Campaign's guidelines for sepsis management (published in JAMA, 2016).

Barmore, W. (2023, May 8). Physiology, urea cycle. StatPearls - NCBI Bookshelf.
https://www.ncbi.nlm.nih.gov/books/NBK513323/#:~:text=The%20urea%20cycle%20is%20the,naturally%20produced%
20by%20gut%20flora.

Professional, C. C. M. (n.d.). Urea cycle Disorder. Cleveland Clinic.

https://my.clevelandclinic.org/health/diseases/23470-urea-cycle-disorder

Urea Cycle Disorder (UCD). (n.d.).

https://www.cincinnatichildrens.org/health/u/ucd#:~:text=The%20liver%20in%20a%20person,damage%2C%20coma%2
0and%20eventually%20death.

Laboratory tests:

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 ● Häberle, J., Boddaert, N., Burlina, A., Chakrapani, A., Dixon, M., Huemer, M., ... & Fuchshuber, A. (2012).
Suggested guidelines for the diagnosis and management of urea cycle disorders. Orphanet Journal of Rare
Diseases, 7(1), 1-14.
● Summar, M. L., Koelker, S., Freedenberg, D., Le Mons, C., Haberle, J., & Lee, H. S. (2013). The incidence of
urea cycle disorders. Molecular Genetics and Metabolism, 110(1-2), 179-180.
● Gropman, A. L., & Batshaw, M. L. (2007). Cognitive outcome in urea cycle disorders. Molecular Genetics and
Metabolism, 90(1-2), 171-178.
● Brusilow, S. W., & Maestri, N. E. (1996). Urea cycle disorders: diagnosis, pathophysiology, and therapy.
Advances in Pediatrics, 43(1), 127-170.
● Enns, G. M., Berry, S. A., Berry, G. T., Rhead, W. J., Brusilow, S. W., & Hamosh, A. (2007). Survival after
treatment with phenylacetate and benzoate for urea-cycle disorders. New England Journal of Medicine,
356(22), 2282-2292.

Treatment:

1.Urea Cycle Disorder Types: Symptoms & Causes. Cleveland Clinic.

https://my.clevelandclinic.org/health/diseases/23470-urea-cycle-disorder

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