Section 22 Metabolic Disorders

Chapter 22.1 Urea cycle defects

Author: Priyanshu Mathur

Reviewer:

Etiology:

 The urea cycle (also known as the ornithine cycle) is a cycle of biochemical reactions that
produces urea (NH2)2CO from ammonia (NH3).
 Mutations lead to deficiencies of the various enzymes and transporters involved in the urea
cycle and cause urea cycle disorders.

Types of UCDs:
1. ARG1 (Arginase) deficiency
2. Argininosuccinate lyase deficiency
3. Argininosuccinate synthase 1 deficiency
4. Citrin deficiency
5. Carbamoyl phosphate synthetase I deficiency
6. NAGS (N-acetylglutamate synthase) deficiency
7. ORNT1 (Ornithine translocase) deficiency
8. OTC (Ornithine transcarbamylase) deficiency

Epidemiology:

 The estimated incidence of urea cycle disorders is 1 in 8500 births.

 Because many cases of urea cycle disorders remain undiagnosed and/or infants born with the
disorders die without a definitive diagnosis, the exact incidence of these cases is unknown and
underestimated.
 Some children with autism spectrum and behavioral disorders may have undiagnosed urea cycle
disorders.

Signs and symptoms:

UCDs fall into two groups:

Complete Urea cycle defect:

 In complete urea cycle defect symptoms starts in first couple of days.
 Child may have refusal to feeds, vomiting, low body temperature, sleepy or sluggish and
problems with posture, seizures, fast breathing and coma.
Partial UCD:
 Baby may not have any symptoms for months or even years. A buildup of ammonia
(hyperammonemia) can happen from illness, injury, stress, or quick weight loss.
 Symptoms may include include: Avoiding foods high in protein or a dislike of meat, loss of
appetite, nausea or vomiting, behavior problems including hyperactivity and mental problems
(confusion, delusions, hallucinations and psychosis).

Diagnosis:

 It can be suspected in patients presented with hyperammonemia and positive family history.
 Urea cycle defects can be screened by routine newborn screening (MS/MS).
 Amino acid levels in blood and urine may help in confirmation of diagnosis.
 Liver biopsy and enzyme assay on biopsy sample can be done to confirm the diagnosis.
 Genetic tests can be used to confirm the diagnosis.

Differential diagnosis:

1. Sepsis
2. Congenital viral infection
3. Duct-dependent heart disease
4. Drug withdrawal
5. Congenital adrenal hyperplasia.
6. Amino acid disorders
7. Organic acidemias
8. Fatty acid oxidation defects
9. Mitochondrial disorders, and
10. Disorders of carbohydrate metabolism

Treatment:

Acute management:

Principles of management:

1. Stop protein intake, reduce catabolism.

2. Remove ammonia (drugs, extracorporeal detoxification).
3. Replenish urea cycle intermediates with arginine or citrulline.
4. Support urinary ammonia excretion by generous fluid intake and consider forced diuresis.

Over first 2 hours:

1. Glucose 10 mg/kg/min (10% solution: 12 ml/kg/2 hrs) with appropriate electrolytes.

2. Arginine hydrochloride 360 mg/kg (= 2 mmol/kg = 2 ml/kg of 1 M solution).
 3. Na-benzoate 250 mg/kg (if available: Additional Na-phenylacetate 250 mg/kg or oral [i.v.] Na-
phenylbutyrate 250 mg/kg).
4. Carnitine 100 mg/kg (less when fatty acid oxidation disorder may be present).
5. Consider Ondansetron 0.15 mg/kg i.v. bolus in the non-comatose child (infusion can lead to
nausea and vomiting).
6. Arginine, Na-benzoate and carnitine may be mixed in glucose 10% and administered as a bypass
to the regular infusion.
7. Check glucose, add insulin if necessary; check ammonia after 2 hrs.
8. Oral carbamyl glutamate 100 mg/kg/day in 3 doses in patients with biochemical findings
suggestive of CPS I or NAGS deficiency.
9. Extracorporeal detoxification: start urgently if NH3 > 500 μmol/l (> 850 mg/dl). Use
haemodiafiltration if available, otherwise haemofiltration or haemodialysis. Peritoneal dialysis is
not efficient.

Long term management:

1. Maintain anabolic state.

2. Limit protein intake: If possible provide minimal requirements as normal protein; if necessary
replace natural protein (contains approx. 50% essential amino acids) by half the amount of an
essential AA mixture.
3. Give arginine 100–200 mg/kg/day (OTC/CPS deficiency) or up to 600 mg/kg/day (ASS/ASL
deficiency). Citrulline (oral) 100–200 mg/kg/day is an alternative in severe OTC/CPS deficiency
(eliminates an additional ammonium group).
4. Remove ammonia: Na-benzoate 250–400 mg/kg/day oral (elimination of 1 mol NH3 per mol of
glycine) and/or Na-phenylbutyrate 250–500 mg/kg/day oral (elimination of 2 mol NH3 per mol
of glutamine).
5. Give vitamins and trace elements (e.g. folic acid 500 μg/day)
6. If carnitine is low: Carnitine 30–50 mg/kg
7. Consider lactulose (binds intestinal ammonia due to acid pH)
8. Monitor laboratory values frequently (initially daily) and adjust diet to avoid excessive protein
reduction (overtreatment).
9. Sufficient fluid intake.
10. Vaccinations as recommended, plus vaccinations against varicella, hepatitis A and influenza.
11. Treat infections early, if necessary ““blindly”” with antibiotics

Prevention:

1. Genetic counselling, calculation of recurrence risk and prenatal diagnosis.

2. Newborn screening for early diagnosis and limiting disability.