UREA

CYCLE
DEFECTS
(UCD)
Congenital
Hypothyroidism (CH)

What are Urea Cycle Defects?

The urea cycle is the main pathway of the body to dispose of excess nitrogen. It allows for the conversion of
ammonia into urea that can be excreted into the urine. Citrullinemia and Argininosuccinic Aciduria are inherited
in an autosomal recessive manner. Citrullinemia occurs as a result of argininosuccinic synthase deficiency while
argininosuccinic aciduria is due to a deficiency of argininosuccinic lyase. Both conditions may manifest with
tachypnea, lethargy, vomiting, irritability, seizures, coma and ultimately death if left untreated. The increased levels
of ammonia may cause brain damage.

Due to blocks in the urea cycle owing to the enzyme deficiency, patients with UCD have low levels of arginine. This
makes arginine an essential amino acid among patients with UCD.

Urea Cycle Defects include:

• Citrullinemia (CIT)
• Argininosuccinic Aciduria (ASA)

Urea Cycle Defects Confirmatory Testing

Citrullinemia (CIT) Plasma amino acids and urine organic acids
Argininosuccinic Aciduria (ASA) Plasma amino acids and urine organic acids

Further confirmatory testing may be required after referral to a metabolic specialist.

Treatment of Urea Cycle Defects

Treatment is through the dietary restriction of protein and the supplementation of a protein free formula. Sodium
benzoate, an ammonia scavenger, is given as well as arginine supplementation.

Preliminary / Initial Management During Metabolic Crisis

Metabolic crises may be caused by an excess intake of protein, illness, prolonged fasting or stressful situations such
as surgery and severe infection. The goal of treatment is to reverse the catabolic state and prevent essential amino
acid deficiency.

NSRC-INT-053/2022
Fact Sheets for Doctors | Newborn Screening Reference Center
 UREA CYCLE
DEFECTS Citrullinemia (CIT)
(UCD)
What is Citrullinemia (CIT)?
Citrullinemia is an inborn error of metabolism resulting from the deficiency of arginosuccinate synthetase, an
enzyme pre- sent in all tissues but the level of which is highest in the liver where it functions in the urea cycle.

CLINICAL MANIFESTATIONS Overview of Disease

Management
Following a brief hiatus in which the newborn appears
normal, anorexia, vomiting and therapy develop followed Long-term steady state management can usually
rapidly by progression to deep coma. The symptoms be provided with arginine (250 mg/kg/day in
mimic that of sepsis and affected newborns present with divided doses), sodium benzoate (250 mg/kg/day
severe lethargy, poor feeding to respiratory distress, in divided doses), and a diet modestly restricted
jitteriness and seizures. in protein.3 Initiation of management should be
done in consultation with an attending physician/
A late onset form may occur as late as 20 years old and metabolic specialist.
present as symptoms such as slurred speech, irritability,
insomnia or delirium.3 Prognosis
Prognosis for intellectual development depends
PATHOPHYSIOLOGY on the nature of the initial hyperammonemia
especially its duration or those of recurrent
episodes.3
Argininosuccinate synthase is an enzyme that converts
citrulline to arginosuccinate, the absence of which causes Preliminary / Initial Management
an increase in plasma citrulline and ammonia levels.
During Metabolic Crisis
Inheritance: autosomal recessive Metabolic crises may be caused by illness,
prolonged fasting or stressful situations such as
surgery and severe infection. The goal of treatment
CONFIRMATORY TESTING is to reverse the catabolic state, correct the acidosis
and prevent essential amino acid deficiency.

Plasma amino acids and urine organic acids. Further

confirmatory testing may be required once referral to a
metabolic specialist is done.

NSRC-INT-053/2022
Fact Sheets
Fact Sheet forfor Doctors
Doctors | Newborn
| Newborn Screening
Screening Reference
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 UREA CYCLE
DEFECTS Citrullinemia (CIT)
(UCD)

WHAT TO DO

If unwell and cannot tolerate oral intake: If unwell and can tolerate oral intake:

• Nothing per orem • Insert oro- or nasogatric tube and start continuous
• Ensure patient’s airway is secure feeding with protein free formula at maintenance rate
• Insert IV access. Collect sample for serum ammonia. • Insert IV access. Collect sample for serum ammonia
May request for investigations (i.e. CBC, etc.) as Monitor glucose levels. May request for investigations
needed. as needed.
• May give fluid boluses if patient requires. • Start D12.5% 0.3NaCl at 5-10 cc/hr
• Start D12.5% 0.3NaCl at full maintenance. Assess • Start IV sodium benzoate loading dose (250mg/kg) to
patient clinically, if there is need to increase fluid, may run for 1-2 hours
do so up to 1.2 or 1.5x the maintenance. • Start IV arginine loading dose (250mg/kg) to run for
• Start IV sodium benzoate loading dose (250mg/kg) to 1-2 hours
run for 1-2 hours • Monitor input and output strictly (q6 hours).
• Start IV arginine loading dose (250mg/kg) to run for
1-2 hours
• Monitor input and output strictly (q6 hours).

*Children should not be protein restricted for longer than necessary (24-48 hours)
*If the patient does not improve with the initial management (within 12 hours), hemodialysis may be indicated.
i Monitor pa- tient clinically, the necessity of hemodialysis will depend on the patient’s clinical status.
*Inform the metabolic doctor on call for further guidance regarding on-going management
*If the patient is well, coordinate with a metabolic specialist regarding further management.

Normal breakdown
of protein
vs
Citrullinemia patient’s
breakdown of protein

1
Su TS, Bock HGO, Beaudet AL et al. Molecular analysis of argininosuccinate syntehtase deficiency in human fibroblasts. J Clin Invest 1982:70:1334-1339.
2
Nyhan WL, Barshop BA and Ozand P. Chapter 31: Citrullinemia. Atlas of Metabolic Diseases 2nd ed. Great Britain:Oxford University Press, 2005 pp 210-213.
3
Wasant P, Viprakasit V, Srisomsap C et al. Argininosuccinate synthetase deficiency: mutation analysis in 3 Thai patients. Southeast Asian J Trop Med Pub Health
2005;36(3):757-761.
4
Nyhan WL, Barshop BA and Ozand P. Chapter 32: Arginosuccinic aciduria. Atlas of Metabolic Diseases 2nd ed. Great Britain: Oxford University Press, 2005 pp 216-219.
5
Schulze A, Matern D, Hoffmann GF. Chapter 2: Newborn screening in Sarafoglou K, Hoffman GF and Roth KS (eds). Pediatric Endocrinology and Inborn Errors of
Metabolism. New York: McGraw Hill, 2009 pp 17-32.

NSRC-INT-053/2022
Fact Sheets
Fact Sheet forfor Doctors
Doctors | Newborn
| Newborn Screening
Screening Reference
Reference CenterCenter