Urea Cycle Disorders

Question 1

The urea cycle rids waste ______ from the body

Answer 1

ammonia

Question 2

In the absence of a functioning urea cycle, ammonia rises and is toxic to the ________

Answer 2

central nervous system

*Encephalopathy, coma, irreversible neurologic damage, or death may result

Question 3

NH3 may be elevated in

Answer 3

Urea cycle disorders (primary)*

Organic acidemias
Fatty acid oxidation disorders
Carnitine cycle disorders 
Liver failure
Valproate therapy

Question 4

The most common urea cycle disorder

X-linked

Answer 4

Ornithine Transcarbamylase (OTC) Deficiency

Question 5

Normal at birth but (for severe disease) can develop hyperammonemia within first few days of life

• Cerebral edema
• Lethargy, anorexia
• Hyperventilation early on (Ammonia stimulates hyperventilation–> respiratory alkalosis)
• Hypoventilation as cerebral edema progresses and compresses brainstem
• Hypothermia
• Recurrent vomiting
• Seizures, neurologic posturing
• Psychosis/hallucinations

Answer 5

Urea Cycle Disorders

Question 6

Acute hyperammonemia RX

Answer 6

• Dialysis and hemofiltration
• Ammonia scavenging drugs: (sodium phenylacetate, sodium benzoate)
• Limit dietary protein
• Administer arginine or citrulline as appropriate
• liver xplant may be needed

Question 7

Male hemizygotes with no enzyme activity may not survive the newborn period

15% of female heterozygotes will have clinical symptoms ranging from mild to severe

Answer 7

Ornithine Transcarbamylase (OTC) Deficiency

Question 8

Plasma amino acids:
Low citrulline
Elevated glutamine (>1200 uM)

Urine organic acids: Elevated orotic acid

Molecular genetic testing of OTC
Hemizygote for p.T178M mutation

Answer 8

Diagnostic for OTC deficiency

Question 9

Ammonia Scavenging Agents

Answer 9

Sodium Phenyacetate

Sodium Benzoate

Question 10

Newborn screening detects many, but not all, disorders of amino acid metabolism

Answer 10

aminoacidopathies, urea cycle disorders, and disorders of organic acid metabolism

Question 11

Urea cycle defects can present at any age

check an ammonia level for unexplained: _______

Answer 11

vomiting, seizures, progressive obtundation

Question 12

Newborn screening does not detect all disorders of the urea cycle; always test if there is a clinical concern: ____________

Answer 12

plasma ammonia, plasma amino acids, urine orotic acid, urine amino acids

Question 13

Plasma ammonia >150 umol/L with a normal anion gap and normal glucose
Serum amino acids: low citrulline, high glutamine
Urine organic acid: elevated orotic acid
Mutation on molecular analysis

Answer 13

OTC Deficiency

Ornithine Transcarbamylase

Question 14

• Plasma ammonia >150 umol/L with a normal anion gap and normal glucose
• Mutation on molecular analysis
• 4 diseases

Answer 14

CPS1 Deficiency– Carbomylphosphate Synthetase I

NAGS Deficiency- N-acetyl glutamate synthetase

ORT-1 Deficiency– Ornithine translocase (transporter)

Citrin Deficiency- (transporter)

Question 15

• Plasma ammonia >150 umol/L with a normal anion gap and normal glucose
• Mutation on molecular analysis
• High citrulline

Answer 15

Citrullinemia Type I/ASS1 Deficiency

Argininosuccinate Synthetase I

Question 16

• Plasma ammonia >150 umol/L with a normal anion gap and normal glucose
• Mutation on molecular analysis
• High citrulline
• Enlarged hepatocytes on biopsy, which may progress to fibrosis
• May have AST/ALT elevations

Answer 16

Argininosuccinic Aciduria/ASL Deficiency

Argininosuccinate Lyase

Question 17

• Plasma ammonia >150 umol/L with a normal anion gap and normal glucose
• -Mutation on molecular analysis
• High arginine

Answer 17

ARG Deficiency

Arginase

Question 18

• Autosomal Recessive

- Most severe (develop hyperammonemia in newborn period and are chronically at risk for repeated bouts)

Answer 18

CPS1 Deficiency– Carbomylphosphate Synthetase I

Question 19

• Autosomal Recessive

- Severe disease but still able to incorporate some waste nitrogen into urea cycle intermediates

Answer 19

Citrullinemia Type I/ASS1 Deficiency– Argininosuccinate Synthetase I

Question 20

• -Autosomal Recessive
• -In addition to hyperammonemia, has also have chronic hepatomegaly and trichorrhexis nodosa (node like appearance of fragile hair)

Answer 20

Argininosuccinic Aciduria/ASL Deficiency

Argininosuccinate Lyase