Kingdom of Saudi Arabia

Ministry of Education
AL-Baha University
Applied College in Baljurashi

Lecture 3
Urea Cycle Disorders
Presented by: Fadiyah Algethami, RD, Msc

Lecturer at Applied College, AL-Baha University

Objectives
At the end of this topic students will be able to know:

• Definition of urea cycle disorders.

• Clinical signs of elevated ammonia.

• Common defects in urea cycle.

• Diagnosis of urea cycle disorders.

• Medical treatment of urea cycle disorders.

• Medical nutrition therapy for infant with urea cycle defect.

• Dietary management for children with urea cycle disorders.

Introduction

• Protein is maded up of 20 different building blocks called amino acids.

• When protein is eaten it is broken down by enzymes into amino acids.

• These amino acids carry out a variety of functions within the body including growth,
repairing cells and tissues as well as making other body proteins.

• Extra protein is converted in the liver to a chemical called ammonia (NH3) and then,
through a series of steps (known as the urea cycle) into another chemical called urea.

• Urea will pass through the kidneys where it is removed from the body in the urine.
 Urea
Glutamate + acetyl CoA
In the liver
Ammonia (NH3) N-Acetylglutamate synthase
2 (NAGS)

Ornithine Carbamoyl phosphate synthetase + N-acetylglutamate

1
6
Argininase Carbamoyl phosphate
+
Arginine Ornithine

Ornithine transcarbamylase
3
(OTC)
5 Argininosuccinate lyase Carbamoyl phosphate +
Ornithine

Citrulline
4 +
Argininosuccinate Aspartate or Aspartic
Argininosuccinate acid
synthetase
 Urea Cycle Disorders

• Urea Cycle Disorders are inherited metabolic disorders result in a definition of any one of six enzymes
in urea cycle which lead to accumulation of ammonia in the blood.

• High levels of ammonia are toxic and it can enter the brain and damage it.

• If left untreated, high ammonia levels can be life threatening.

• In a person without a urea cycle disorder, ammonia is converted into urea.

• People with a urea cycle disorder are born without or with very little of one of the six enzymes that
breakdown ammonia which results in high levels of ammonia building up in the blood.
 Symptoms of Urea Cycle Disorders
• The clinical signs of elevated ammonia are:

➢ Vomiting
➢ Lethargy
➢ Seizures
➢ Coma, and ultimately death.

• In infants the adverse effects of elevated ammonia levels are rapid and devastating.

• In older children symptoms of elevated ammonia may be preceded by hyperactivity and irritability.

• Neurologic damage may result from frequent and severe episodes of hyperammonemia.

• The severity and variation of the clinical courses of some urea cycle defects may be related to the
degree of residual enzyme activity.
 Common Defect in Urea Cycle

1- Carbamyl-phosphate synthetase (CPS) deficiency

• It is the result of deficient activity of Carbamyl-

phosphate synthase (CPS).

• The onset is usually in the early neonatal period.

Symptomes of CPS deficiency are:

➢ Vomiting
➢ Irritability
➢ Marked hyperammonemia
➢ Respiratory distress
➢ Altered muscle tone
➢ Lethargy
➢ Coma Figure 2: Carbamyl-phosphate synthetase (CPS) deficiency
Common Defect in Urea Cycle

Specific laboratory findings usually include in CPS deficiency:

➢ Low plasma levels of citrulline and arginine.

➢ Normal orotic acid levels in urine

 Common Defect in Urea Cycle

2- Ornithine transcarbamylase (OTC) deficiency

• It is an X-linked disorder marked by blockage in the

conversion of ornithine and carbamyl phosphate to citrulline.

OTC deficiency is identified by:

➢ Hyperammonemia

➢ Increased urinary orotic acid

➢ Normal levels of citrulline, argininosuccinic acid, and

arginine.

Figure 3: Ornithine transcarbamylase (OTC) deficiency

 Common Defect in Urea Cycle

• Because females have two X-chromosomes, the good X can balance out the problem with the
faulty X. But because males only have one X chromosome, it cannot be balanced by a normal X
as in the female and, as a result, in males this disease tends to be more severe.

• Severe OTC deficiency is usually lethal in males.

• Heterozygous females with various degrees of enzyme activity may not demonstrate
symptoms until they are induced by stress, as from an infection, or a significant increase in
protein intake.
 Common Defect in Urea Cycle

3- Citrullinemia

• It is the result of a deficiency of argininosuccinic acid

synthetase in the metabolism of citrulline to argininosuccinic
acid.

• It is identified by markedly elevated citrulline levels in the

urine and blood.

Figure 4: Argininosuccinic acid synthetase deficiency

 Common Defect in Urea Cycle

4- Argininosuccinic aciduria (ASA)

• It is results from deficiency of argininosuccinate lyase,

which is involved in the metabolism of argininosuccinic
acid to arginine.

• ASA is identified by the presence of argininosuccinic acid

in urine and blood.

• l-arginine must be supplemented to provide an alternative

pathway for waste nitrogen excretion.

Figure 5: Argininosuccinic layas deficiency

 Diagnosis of Urea Cycle Disorders

• The onset and severity of urea cycle disorders is highly variable and depends on the
specific enzyme involved as well as also on the ability of that enzyme to work.

• Severe forms result in none or very little enzyme activity and result in severe urea cycle
disorders.

• Mild to moderate forms result when there is some enzyme activity.

Diagnosis of Urea Cycle Disorders

• Newborn babies with severe urea cycle disorders become severely ill shortly after
birth.

• Children with less severe urea cycle disorders may be diagnosed during childhood or
can remain undiagnosed because symptoms are not recognised.

• Adults often go undiagnosed because they have mild urea cycle disorders which allow
them to remove enough ammonia until a stress (e.g. illness) interferes with the ability of
the enzyme to work or causes large amounts of ammonia to be made.
Treatment of Urea Cycle Disorders

Aim of urea cycle treatment:

• To ensure acceptable levels of ammonia and amino acids.

• To provide adequate protein to support normal growth and development.

Outcome in urea cycle:

• Neurologic outcome and intellectual development in individuals with urea cycle disorders
vary, with a range from normal IQ and motor function to severe intellectual disability and
cerebral palsy.
Medical Treatment of Urea Cycle Disorders

• Acute episodes of illness are managed by discontinuing protein intake and administering
intravenous fluids and glucose to correct dehydration and provide energy.

• If hyperammonemia is severe, peritoneal dialysis, hemodialysis, or exchange transfusion

may be required.

• Intravenous sodium benzoate or other alternative pathway compounds have been beneficial in
reducing the hyperammonemia.
Medical Nutrition Therapy (MNT) for infant
with Urea Cycle Disorders

The first few days

• Babies born with urea cycle disorders will have high ammonia levels
initially.

• To reduce ammonia levels, your baby will be given a protein-free formula

instead of breastfeeds or standard infant formula for the first few days after
diagnosis. This will allow the ammonia level to come down quickly.
Protein-free formula (synthetic protein)

• Protein-free formula contains all the nutrients needed for growth, except
protein.
 Medical Nutrition Therapy (MNT) for infant
with Urea Cycle Disorders

Breast feeding

• Breast milk alone contains too much protein for babies with a urea cycle disorder. Therefore,
protein-free formula needs to be given in addition to breast milk.

• A measured amount of protein-free formula +/- a measured amount of synthetic protein are given
first and then breastfeed to appetite.

• If your baby is hungry in between feeds you may give extra breastfeeds in addition to the
measured amounts of protein-free formula +/- synthetic protein.
 Medical Nutrition Therapy (MNT) for infant
with Urea Cycle Disorders

Formula feeding

• If you choose not to, or are unable to breastfeed, standard infant formula is an appropriate
alternative, along with a protein-free formula.

• A measured amount of standard infant formula +/- a measured amount of synthetic protein are
given first and then a protein-free formula to appetite.
Dietary Management for Children with Urea
Cycle Disorders

• The dietary treatment for urea cycle disorders is a low protein diet and this is a diet
for life.

• The diet prevents a build-up of excess ammonia in the blood, while at the same time
providing enough protein for their normal growth and development.

• There are five main components of the diet:

1. Synthetic protein
2. Unwell management
3. Foods to avoid
4. Exchange foods
5. Free foods
Dietary Management for Children with Urea
Cycle Disorders
1- Synthetic protein:

• It is a specially made protein that contains only the essential amino acids.

• Some children with urea cycle disorders are recommended to take a synthetic protein to
ensure that children gets enough of these essential amino acids to grow, build and repair
tissues.

• If too much of this synthetic protein is given, the extra protein that the body does not use
can be converted into ammonia.

• The synthetic protein is an essential part of the treatment of urea cycle disorders. If it is not
taken as recommended, ammonia and amino acid levels, can be outside the acceptable range
which can cause health and growth problems.
Dietary Management for Children with Urea
Cycle Disorders

2-Unwell management:

• During illness, the body starts to break down its own body tissue, releasing protein into the
blood stream which rapidly increase ammonia levels.

• Levels of ammonia increase quickly which can make your child very ill quickly . If left
untreated it can become life threatening.

• High ammonia levels can be reduced by giving appropriate dietary management and high
calorie drinks.

• The natural protein will be either reduced or stopped.

• Synthetic protein may also be stopped, as it can contribute to high ammonia levels.
 Dietary Management for Children with Urea
Cycle Disorders

3- Foods to avoided:

• High protein foods such as meat, fish, chicken, eggs, milk, cheese, yogurts, soya, nuts,
bread, flour-based products such as pasta, cake and biscuit as well as jelly, jellies and
sweets containing gelatine are high in protein and so are not allowed.
Dietary Management for Children with Urea
Cycle Disorders

4. Exchange foods

• Child requires a small amount of protein for growth, development and repair.

• Foods such as cereals, rice, beans, peas and potatoes contain a small amount of
protein and given in small measured quantities called exchanges.

• An exchange is the amount of any food that contains 1 gram of protein.

• Every child will have a set number of exchanges per day is depended on their
blood ammonia and amino acid levels.
Dietary Management for Children with Urea
Cycle Disorders

5. Free foods

• Naturally low in protein food such as most fruit and vegetables, butter,
margarine, cooking oils, jam, sugar and honey (honey is not recommended
for any infant under 12 months) can be eat freely.

• Manufactured low protein foods such as bread, pizza bases, pasta, rice,
flour, cereals, milk, meat substitutes, cake mixes, biscuits and chocolate.
References:

Metabolic dietitian (2019) ‘Urea cycle disorder’, National Centre for Inherited Metabolic
Disorders, Temple Street Children’s University Hospital, pp. 1–68.

Kathleen, L. M. and Janice, L. R. (2017) Krause’s Food & The Nutrient Care Process,
Elsevier.
THANKS