Urea Cycle Disorders

Question 1

What is the function of the urea cycle?

Answer 1

It is the main route for the detoxification of ammonia

Question 2

What do defects in urea cycle result in?

Answer 2

Hyperammonemia

Question 3

Where is the complete urea cycle found?

Answer 3

Peripheral hepatocytes

Question 4

What is involved in the urea cycle?

Answer 4

3 cytosolic enzymes
2 mitochondrial enzymes
Ornithine/citruline anti potter
N acetylglutamate synthase

Question 5

What causes urea cycle disorders?

Answer 5

Loss of function of urea cycle enzymes and urea cycle related enzymes

Question 6

Mention the urea cycle enzymes

Answer 6

Carbamoyl phosphate synthase
Ornithine trans carbomylase
Arginosuccinate synthase
Arginase

Question 7

What are the urea cycle related enzymes?

Answer 7

Mitochondrial Ornithine/Citrulline antiporter
N-acetylglutamate Synthase
Arginosuccinate Synthase (ASS)-CPS activating enzyme

Question 8

What is the inheritance of urea cycle disorders?

Answer 8

All EXCLUDING OTC are Autosomal Recessively Inherited while OTC is X-linked

Question 9

Classify urea cycle disorders

Answer 9

Cytosolic Urea Cycle disorders
Mitochondrial Urea Cycal Disorders

Question 10

What is the most common mitochondrial urea cycle disorder

Answer 10

OTC>CPS>NAGS

Question 11

What is the role of the NAGS 1 enzyme and what does this suggest?

Answer 11

NAGS 1 produces essential activator of CPS1 so it’s deficiency is clinically indistinguishable from CPS1

Question 12

Mention the features of acute hyperammonemia

Answer 12

Irritability
Inability to feed or refusal to feed
Vomiting
Hypotonia
lethargy
convulsions
Coma
Death
Neurological Sequelae
Developmental Delay
Mental Retardation
Abnormal Behaviour
Neuro- Psychatric Manifestations

Question 13

What is the clinical presentation of mitochondrial urea cycle disorder

Answer 13

Hyperammonemia-encephalopathy
Vomiting
refusal/inability to feed
stupor
somnolence
hypotonia
seizures
hyper/ hypoventilation
Respiratory Alkalosis - very common Liver failure/Coagulopathy
Developmental Delay
Mental Retardation
Abnormal Behaviour
Neuro-Psychatric Manifestations

Question 14

What happens in mitochondrial urea cycle disorder?

Answer 14

cittrulline production is reduced or absent hence [Cittrulline] is low or absent

NH3 can’t be incorporated into Carboamyl Phosphate hence Hyperammonemia

NH3 enters freely into the brain and is neutralised

NH3 is converted into NH4 leading to Brain edema

Question 15

How many mutations can there be for CPS and OTC?

Answer 15

CPS - >230 mutations
OTC - >500 mutations

Question 16

How would you diagnose MUCD

Answer 16

Hyperammonemia without hypoglycaemia

Plasma Ammonia 400-500umol/L

Glutamine and Alanine are raised

Citrulline and Arginine are reduced

DNA Sequencing

Question 17

How would you treat MUCD

Answer 17

Stop exogenous protein
High calorie diet
Reduce NH3/NH4 with medication or dialysis
NaBenzoate or NaPhenylacetate 250mg/kg in 90-120 mins with maintenance infusion of 250-500mg/kg/day
L-Arginine 250 mg/kg in 90-120 mins maintain at 250 mg/kg
NH3 determination 3 hourly if > 500umol/L-dialysis

Question 18

Maintenance treatment for MUCD

Answer 18

NAGS deficiency-near cure with N-Carbmyl-L-Glutamate (Carglumic or CarGlu)-Synthetic analogue of CPS1

NAG Po4-100 mg/kg/day in 3 divided doses prior to meals CPS1+OTC-

Low protein diet

If frequent crises-liver transplant @ > 3 months of age or > 5 kg

NaBenzoate or NaPhenylbuturate 200-250 mg/kg in three divided doses

Glycerol Phenylbutyrate tastes better (PavicitXX)

L-Arginine or L-Citrulline 100-200 mg/kg/day in 3 divided doses

Question 19

Describe the presentation of CUCD

Answer 19

Clinically indistinguishable from MUCD’s

ARG1-rare in newborns may also present with cholestasis
Marked hepatomegaly

Brittle hair from secondary Arginine deficiency

Arterial hypertension in adolescents and adults

Question 20

How would you make a diagnosis of CUCD

Answer 20

increased plasma and urine levels of Citrullline, Arginosuccinate and Arginine

Increased plasma citrulline greater than 500 umol/L is pathognomonic for ASS

Arginosuccinate with or its too anhydrides in plasma and Urine is pathognomonic for ASL

Elevated Arginine implies ARG1 deficiency

RBC enzyme studies

NBS-tandem mass arrays

Question 21

How would you treat CUCD

Answer 21

Arginosuccinate Lyase Deficiency ASLD-iv L-Arginine 400 mg/kg over 90-120 mins followed by maintenance infusion of 400 mg/kg/day

Maintenance for ASS & ASL is as for CPS1 and OTC

NaBenzoate or NaPhenylacetate 250-500mg/ kg/day in 3 divided doses

L-Arginine 100-300 mg/kg in 3 divided doses low dose regimen

Liver transplant