Urea Cycle and Disorders

Question 1

What is the purpose of the urea cycle?

Answer 1

• primary mechanism of waste nitrogen disposal
• Nitrogen(amino acids from protein catabolism and nucleic acids)–>ammonia–>urea excreted by kidneys
• 2 ammonia+CO2 +3ATP→ urea+water+3 ADP

Question 2

How does nitrogen enter the urea cycle?

Answer 2

1. Transamination 2. Oxidative deamination
   Nitrogen is converted to ammonia to enter urea cycle. Important enzymes:
   ALT and AST= enzyme levels indicators of liver damage

Question 3

What are the dangers of hyperammonemia?

Answer 3

• can enter the brain by diffusing from blood or CSF–>brain swelling
• NH4+ ions can disrupt ion gradients, neurotransmitters, transport of metabolites, mitochondrial function, and alter ratio of alpha ketoglutarate/glutamate/glutamine

Question 4

What are clinical findings of hyperammonemia?

Answer 4

-Early Symptoms Include:
Irritability
Lethargy
Vomiting
-Progressive Hyperammonemia Results In:
Stupor, seizures, decerebrate and decorticate posturing
Cerebral edema, increased intracranial pressure, brain stem herniation
Apnea
Death

Question 5

What are the acquired causes of hyperammonemia?

Answer 5

--Liver Failure
Acute Liver Failure:	
Fulminant viral hepatitis
Drug/Toxin Injury
-Acetaminophen, Valproic acid, Salicylates, Chemotherapeutic agents, Mushroom poisoning
Asphyxia
-Chronic Liver Failure:
Cirrhosis  (Chronic viral hepatitis, alcoholic cirrhosis)
-Reye’s Syndrome

Question 6

What are the inherited causes of hyperammonemia?

Answer 6

Organic Acidemias:
-Proprionic acidemia
-Methylmalonic acidemia
Fatty Acid Oxidation Disorders

Question 7

What is the clinical course of urea cycle disorders?

Answer 7

• Absence/severe of any of first 4 enzymes. Rapid onset of symptoms during first few days of life
• Milder or partial absence-symptoms during illness or stress related to less eating and increased muscle protein breakdown or increased protein intake
• Arginase deficiency-rarely assoc with early severe symptoms. Slowly progressive neurologic symptoms.

Question 8

Symptoms of urea cycle disorders early onset versus late onset

Answer 8

• early onset: infants appear normal at birth, after feeding–>vomiting, irritability, progressive lethargy–>seizures, hypotonia, respiratory distress, coma, death if untreated
• late onset: irritablity, hyperactivity,Protein avoidance, Delayed development, Intellectual impairment, Recurrent emesis, Seizures, Illness-induced hyperammonemia

Question 9

How are urea cycle disorders treated?

Answer 9

• dietary restriction
• hydration, IV glucose during acute attacks
• avoid drugs known to cause liver damage or interfere with urea cycle
• nitrogen removal: e.g. glycerol pheynylbutyrate, na benzoate, na phenylbutyrate
• liver transplantation
• gene therapy

Question 10

Most common enzyme mutation for urea cycle disorder?

Answer 10

Ornithine Transcarbamylase Deficiency